There is a continuing, unfilled need for improved endoscopic techniques, methods and apparatus to obtain optical images of tissue inside a patient, while minimizing the patient's discomfort and minimizing any damage caused by the imaging probe itself. In particular, there is an unfilled need for a forward-looking, optical coherence tomography endoscope probe having a small outer diameter. Existing probes are either side-firing, or if forward-looking have a large diameter or otherwise have an unduly complex construction.
One example of the many conditions for which there is a need for improved endoscopic techniques is gastric cancer. Gastric cancer is the fourth most common cancer and the second leading cause of cancer death in humans worldwide. About 90% of stomach tumors are adenocarcinomas, which are subdivided into two main histological types: 1) well-differentiated- or intestinal-type, and 2) undifferentiated- or diffuse-type. Recently, the incidence of intestinal-type tumors of the stomach has decreased, but the incidence of diffuse-type gastric carcinomas has increased. In general, countries with higher incidence rates of gastric cancer, such as Japan, have better survival rates than countries with lower incidence. Early-detection screening in high-risk areas has led to decreased mortality rates. When disease is confined to the inner lining of the stomach wall, 5-year survival is about 95%. Unfortunately, few gastric cancers are discovered at an early stage in the United States, leading to 5-year relative survival rates of less than 20%. Similarly, in European countries, the 5-year relative survival rates for gastric cancer vary from 10% to 20%. Hence, despite major research and clinical efforts, the number of deaths from gastric cancer has not decreased in recent years. A major clinical goal is early detection and surgical excision.
The prognosis for patients with suspected gastric cancer depends strongly on early detection and accurate preoperative staging. Other factors that influence prognosis are the depth of wall invasion, the presence or absence of lymph node metastases and distant metastases. Accurate preoperative evaluation at an early stage offers the best prognosis, and is essential for planning an optimal therapy, including an evaluation of the appropriateness of a limited surgery such as endoscopic mucosal resection or laparoscopic surgery. Although diagnostic advances in endoscopy techniques and double-contrast barium studies allow the detection of small lesions early in the course of the disease, the depth of tumor invasion cannot readily be determined by either of these methods. Currently, the preoperative staging of gastric cancer is usually diagnosed by computed tomography (CT). Continued refinement of CT techniques has improved the ability to stage gastric cancer. Nevertheless, results are still not satisfactory, especially for evaluating tumor depth. There is an unfilled need for improved methods to image and stage gastric tumors and other tumors.
Advances in CT scanners and computer technology have made more powerful and affordable 3D imaging systems available. To improve tumor staging by CT, it is essential to precisely locate the tumor. The detection of gastric cancer is influenced by factors including morphologic features, thickening of the gastric wall, and the degree of tumor enhancement. In a CT scan, a lesion is inferred to be cancerous when the gastric wall shows focal thickening, or when the gastric wall has an unusual contrast-enhancement pattern. The depth of tumor invasion on CT is usually classified according to a standard system. The detectability of early gastric cancers by CT is very low, with a rate of 20% to 53%. Accordingly, in most studies that have evaluated staging of gastric cancer, the absence of an abnormal finding on imaging is considered to be the earliest stage of cancer. With the introduction of techniques such as fast scanning, rapid infusion of intravenous contrast medium (dynamic CT scanning), and gastric water filing, the tumor detection rate has markedly increased, because two or three layers of enhanced gastric wall can be visualized. However, even with dynamic CT scanning, it is well known that gastric cancers located on the horizontally-oriented portion of the gastric wall are difficult to detect due to poor z-axis resolution and the partial volume averaging effect. In addition, using CT it is slightly easier to detect protruding early gastric cancers than flat, depressed, or excavated tumors. Although recent improvements in CT techniques have overcome some of the limitations of conventional axial CT, and while they allow improved tumor detection and localization, the detection of early gastric cancers in the absence of a thickened gastric wall remains difficult.
Optical coherence tomography (OCT) is an emerging branch of endoscopy. Optical coherence tomography (OCT) is an imaging technique that uses backscattered light to obtain cross-sectional images of tissue. It is analogous to ultrasound imaging, except that near-infrared light is used rather than sound, and the signal is generated at optical discontinuities rather than acoustic discontinuities. Conventional OCT is an outstanding technique for imaging superficial tissue. It can be used to obtain in vivo cross-sectional or even volume images within body cavities and tissues. OCT typically has a resolution of 5-20 μm, and a depth of penetration of 1-2 mm. The axial resolution, along the line of sight, is determined by the light source and detection electronics. This has historically tended to be comparable to the transverse resolution, which is determined by the optical system. OCT lacks cellular resolution but is able to visualize subsurface structures associated with early stage cancers and other diseases, such as epithelial thickening and abnormal glands. OCT has been used to image a variety of tissues that can be accessed either directly or via endoscope or catheter. For instance, pilot studies have indicated that OCT can detect early neoplastic changes in the colon, skin, and esophagus, and thin-capped fibroatheroma. OCT has been used to image pathologies of the retina.
OCT has been used for in vivo endoscopic imaging of human stomach. It has been used to image glandular epithelium, muscularis mucosa, submucosa, and muscularis propria, gastric pits, and highly reflective lamina propria. Optical coherence tomography systems may be used, for example, in studying the microvasculature, skin, tendon, ovary, and colon of animal models and human patients. It has been reported that OCT images are superior to those from ultrasound in visualizing superficial layers of the stomach. Doppler OCT, a variant sensitive to Doppler shifts caused by moving blood cells, has been used to image pathologies of the gastrointestinal tract, variations in tissue structure, and blood vessel anatomy. To our knowledge, no prior OCT imaging has successfully visualized gastric submucosa.
Micro-electro-mechanical systems or MEMS employ devices or systems built using microfabrication processes similar to those used to fabricate integrated circuits (ICs). Many MEMS devices have entered into mass production and have established markets. However, MEMS is still a young technology, especially in the biomedical applications.
In a graded index lens (“GRIN lens”) the index of refraction changes as a function of position. Most GRIN lenses are cylindrical rods in which the index of refraction decreases with distance from the axis. For example, one GRIN lens that may be used in the present invention is a commercially available lens 1 mm in diameter, whose refractive index, n, is a parabolic function of the radial distance, r, from the cylindrical axis:
      n    ⁡          (      r      )        -            n      0        ⁡          (              1        -                              A            2                    ⁢                      r            2                              )      For a commercially-available lens that we used in a model of the present invention (NSG Europe, Temse, Belgium), in the above equation A=0.3564 and no=1.5916 (the index of refraction on-axis.) Much of the focusing takes place within the body of the GRIN lens. In a GRIN lens with a parabolically-varying index of refraction, it can be shown that a ray of light follows a sinusoidal path in the lens. GRIN lenses are often sold in lengths that correspond to the number of oscillations of this sine wave. For example, a ray in a lens of length “2π” will undergo one complete oscillation of the sine wave, and a lens of length “π/2” will undergo one quarter of an oscillation, or 90° of oscillation. FIG. 1 depicts a ray trace for two beams with NA=0.12 through a “π/2” lens. Both beams enter the lens parallel to the axis, one at a radius r=0, and the other at r=0.4 mm. The rays in the beams follow sinusoidal paths. At the length π/2 (2.63 mm) both beams are centered on the axis of the lens, and the spread of both lies within ±0.134 mm of the axis. At the length π/2, the rays from a given beam are all parallel to one another (although the direction of the rays will, in general, differ from the direction of rays from a different starting beam). The length π/2 corresponds roughly to a conventional lens plus a focal distance, since a point source at one end is transformed into a parallel beam at the other (and vice versa).
A GRIN lens of length “π/2” may also be used to image objects located outside the lens. FIG. 2 depicts an example of 1:1 imaging with a π/2 lens, with an object point and an image point each spaced 1.57 mm from opposite sides of the GRIN lens. In this example the index of refraction on either side of the lens is 1.5, approximately the average of the varying index within the lens. The sinusoidal paths shown inside the lens are parallel at its midpoint (π/4), and they converge symmetrically to the object and image points.
There are two principal types of OCT endoscopes: forward-looking, and side-scanning. A side-scanning endoscope is useful to examine tubular organs. A forward-looking endoscope can be used to image a hollow organ or a tissue that has at least one wall that is perpendicular, or nearly perpendicular, to the axis of the scope. Forward-looking endoscopes have the advantage that they can look ahead and collect data before entering and possibly damaging the tissue. Transverse scanning in OCT endoscopes has been conducted by rotating the entire fiber-optic assembly with an external motor, and also by scanning a mirror with an internal galvanometric motor. In prior forward-looking endoscopes the mechanisms used to scan have either required relatively wide probes, or the design of the probes makes them prone to vibration, neither of which is desirable. The forward-looking endoscopes that have been reported to date are typically a few mm in diameter. Reducing the diameter of the probe can help minimize tissue damage, but to our knowledge the narrowest forward looking probes reported previously have been about 1.65 mm in diameter. It would be desirable to reduce the diameter to 1.5 mm, 1.25 mm, 1 mm or even smaller, but such a small diameter is difficult to achieve with existing designs.
Some OCT endoscopes have been built using MEMS technology, both for side-scanning and forward-looking OCT. The reported devices have used either electrostatic actuators or electro-thermal actuators. Reported probes to date have shown an axial resolution of 4˜13 μm, a transverse resolution of 13˜35 μm, and an imaging speed of 5˜20 frame/sec with either 2- or 3-dimensional imaging capability. However, the outside diameter of these probes has usually been in the range of 4 to 6 mm, though some are smaller. There is an unfilled need for further miniaturization of such optical probes, preferably with a diameter ˜1.5 mm or smaller, to penetrate through small body cavities and to minimize damage to tissues.
A scanning mechanism is required to have a useful OCT probe. Yet, a scanning mechanism tends to increase the diameter of the probe, which is undesirable, or it results in a sideways-looking probe rather than a forward-looking probe. Placing a mirror in line with a GRIN lens at a 45° angle preserves the small diameter of the probe, but results in a sideways-looking probe. While a side view can be helpful in some situations, a forward-looking probe is more generally useful. Other types of forward-looking probes that have been reported include one in which a distal scanning mirror is placed alongside a GRIN lens, which approximately doubles the diameter of the probe; and one in which a complex counter-rotation system with two GRIN lenses is employed, which is mechanically complex, rigid, and may be prone to vibration.
Side-firing endoscopes are disclosed, for example, in W. Jung et al., “Three-dimensional endoscopic optical coherence tomography by use of a two-axis microelectromechanical scanning mirror,” Appl. Phys. Lett., vol. 88, pp. 163901-1 through -3 (2006); C. Chong, “Optically modulated MEMS scanning endoscope,” IEEE Photonics Tech. Lett., vol. 18, pp. 133-135 (2006); and J. Yeow et al., “Micromachined 2-D scanner for 3-D optical coherence tomography,” Sensors and Actuators A, vol.117, pp. 331-340 (2005).
J. Wu et al., “Paired-angle-rotation scanning optical coherence tomography forward-imaging probe,” Optics Letters, vol. 31, pp. 1265-1267 (2006) discloses a forward-scanning OCT system that uses a pair of rotating, angled, gradient-index lenses to scan the output probe beam. A prototype probe was reported with an outer diameter of 1.65 mm, with the two lenses rotating at equal and opposite angular speeds of ˜21 rpm. Because lenses with relatively high masses rotate rapidly through 360 degrees, as opposed to scanning through relatively smaller angles with a relatively low-mass mirror, this probe may be prone to undesirable vibrations and may, perhaps, be less reliable mechanically as compared to designs based on lower-mass scanning mirrors. The probe must presumably be rigid to accommodate this design.
T. Xie et al., “Endoscopic optical coherence tomography with new MEMS mirror,” Elect. Lett., vol. 39, pp. 1535-1536 (2003) discloses a forward-scanning OCT probe in which a MEMS scanning mirror is positioned more-or-less adjacent to a GRIN lens. The outer diameter of the probe was 4.3 mm. From the design depicted in FIG. 1 of that paper, it can be seen that the diameter will necessarily be substantially greater than that of the lens alone, since the probe must accommodate the lens and the mirror side-by-side.
X. Liu et al., “Rapid-scanning forward-imaging miniature endoscope for real-time optical coherence tomography,” Optics, vol. 29, pp. 1763-1765 (2004) discloses a forward-scanning OCT probe having an outer diameter of 2.4 mm. Scanning was achieved by coupling a fiber-optic cantilever, positioned behind a GRIN lens, to a vibrating actuator. The design of the probe makes it inherently prone to vibration, and may make it difficult to implement three-dimensional scanning.
T. Xie et al., “GRIN lens rod based probe for endoscopic spectral domain optical coherence tomography with fast dynamic focus tracking,” Optics Express, vol. 14, pp. 3238-3246 (2006) discloses forward-scanning and side-firing OCT probes based on gradient index lenses. Light from a single-mode fiber was steered by a servo mirror on the proximal end of the GRIN lens to perform a lateral scan on the entrance plane of the GRIN lens rod. The focal depth was varied dynamically without moving the probe, from a depth of 0 to 7.5 mm. The lateral scanning range was reported to be up to 2.7 or 4.5 mm, as determined by the diameter of the GRIN lens rod itself. This type of endoscope is rigid, limiting usefulness for gastric (and other types of) imaging. See also T. Xie et al., “Fiber-optic-bundle-based optical coherence tomography,” Optics Letters, vol. 30, pp.1803-1805 (2005).